Cannabinoids exert a profound impact on the hypothalamic control of biological processes such as reproduction and energy homeostasis. The overall goal of this proposal is to gain a better understanding of the cannabinoid regulation of appetite, core body temperature, metabolism, and the cellular mechanism(s) by which they affect the excitability of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus to alter these actions. The fundamental hypothesis is that cannabinoids modulate energy balance in a sex-dependent fashion that can be differentially influenced by gonadal steroid hormones. They do so by 1) presynaptically altering the balance between excitatory + and inhibitory neurotransmission and 2) augmenting postsynaptic K currents, thereby reducing POMC neuronal activity in a manner that is sexually differentiated and dependent on the gonadal steroid milieu. Cannabinoid regulation of energy homeostasis and synaptic transmission onto appetite-suppressing POMC neurons will be studied using a guinea pig animal model. Females are ovariectomized and males orchidectomized one week prior to experimentation, respectively. In Specific Aim 1, I will evaluate the mechanisms through which androgens and estrogens differentially modulate the cannabinoid regulation of energy balance by assessing how they influence 1) the capability of CB1 receptor agonists and antagonists to alter food intake, meal pattern, core body temperature, O2 consumption, CO2 and metabolic heat production, 2) endogenous cannabinoid production and subsequent presynaptic inhibition of excitatory glutamatergic and inhibitory GABAergic synaptic input onto POMC neurons, and 3) the activity and expression of critical energy-sensing enzymes, under different dietary and motivational conditions. In Specific Aim 2, the objective is to determine the receptor subtype(s) through which estrogens attenuate the cannabinoid modulation of energy balance. Specifically, I will evaluate whether agonists for the Gq-coupled membrane estrogen receptor m(ER), ER, ER and/or GPR30 diminish cannabinoid-induced changes in energy intake and expenditure, as well the presynaptic inhibition of glutamatergic input onto POMC neurons. This proposal describes an integrated approach to study sex differences in, and gonadal steroid hormonal on, the cannabinoid regulation of energy balance, and will elucidate the relevant cellular mechanisms that predetermine the sensitivity of males and females to the acute perturbation of energy intake and expenditure very early in cannabinoid abuse.